Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.27.5 (RNase)
 17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of 2',5'-oligoadenylate synthetase, an enzyme recently discovered in interferon-treated cells, was found in lymphocytes from normal mouse spleen that had received neither exogenous interferon nor its inducers. The oligoadenylate synthesized by lymphocyte cell extracts inhibited protein synthesis in rabbit reticulocyte lysates. The oligomers were composed mainly of trimer and were resistant to digestion by T2 ribonuclease. The level of the enzyme in lymphocytes was about 20 to 30% of that in L929 cells treated with interferon. The activity of the enzyme was further enhanced in lymphocytes in vitro by addition of interferon. The 2',5'-oligoadenylate synthetase was distributed among several lymphoid tissues, but was not detected in cell extracts from brain or liver. The enzyme may play an important role in the regulation of the immune system.
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PMID:2',5'-Oligoadenylate synthetase activity in lymphocytes from normal mouse. 50 Jun 92

Alkaline ribonuclease (RNase; EC 3.1.27.5) activities and 2',5'-oligoadenylate synthetase (2-5 AS; no EC no. assigned) activities in serum were measured in nine patients with hepatitis B e antigen-positive chronic hepatitis B before, during, and after treatment with recombinant human interferon alpha-2b for four weeks at daily doses ranging from 3 to 10 mega-units. Alkaline RNase activities in serum significantly increased from 65.8 +/- 9.5 units/L (mean +/- SD) to 84.3 +/- 11.9 units/L after the first week of therapy (P less than 0.001). (One unit of RNase activity is defined as that increasing the absorbance at 260 nm by 1.0 in 1 min). This increase persisted during and until two weeks after the end of the therapy, at which time the mean RNase activity in serum was still significantly increased (70.8 +/- 9.4 units/L, P less than 0.01). Before therapy, phosphocellulose chromatography of RNase showed five active peaks of enzyme activity, which were similar to that observed even when RNase activity increased immediately after therapy. There was a close correlation between RNase activities and the logarithm of 2-5 AS activities, measured simultaneously in each patient. We conclude that recombinant alpha-interferon therapy increases RNase activities in serum, associated with the increased 2-5 AS activities.
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PMID:Effects of recombinant leukocyte interferon on ribonuclease activities in serum in chronic hepatitis B. 235 34

The enzymatic synthesis and characterization of (RP)-2',5'-AMPS trimer and tetramer (SP)-5'-O-(1-thiotriphosphates) from chirally substituted (SP)-[alpha-35S]ATP alpha S by 2',5'-oligoadenylate synthetase from interferon-treated L cell extracts are described. The (RP)-ATP alpha S isomer is not a substrate for the synthetase. The identification of the trimer and tetramer analogues (molar ratio 70:30) was accomplished by high-performance liquid chromatography and subsequent separation by charge using DEAE-cellulose thin-layer chromatography. The digestion of the analogue by snake venom phosphodiesterase I (SVPD) to [alpha-35S]ATP alpha S and [35S]AMPS but not by T2 RNase demonstrated the presence of the 2',5' linkage. The assignment of RP configuration of the 2',5'-phosphorothiodiester linkage was based on the highly specific stereoselectivity of SVPD for RP diastereomers [Burgers, P. M. J., & Eckstein, F. (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 4978-4800; Bryant, F. R., & Benkovic, S. J. (1979) Biochemistry 18, 2825-2828; Nelson, P. S., Bach, C. T., & Verheyden, J. P. H. (1984) J. Org. Chem. 49, 2314-2317]. This suggests that the synthesis of the phosphorothioate analogues proceeded via inversion of configuration at the chiral phosphorus of (SP)-ATP alpha S. The putative (RP)-2',5'-AMPS tetramer (SP)-5'-O-(1-thiotriphosphate) displaced the 2',5'-p3A4[32P]pCp analogue from 2',5'-oligoadenylate-dependent endonuclease 5 times more efficiently than did equimolar concentrations of authentic 2',5'-adenylate tetramer triphosphate. Furthermore, in studies using the calcium phosphate coprecipitation technique, the 2',5'-phosphorothioate trimer and tetramer analogues inhibited protein synthesis better than did 2',5'-adenylate trimer and tetramer triphosphates.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:2',5'-Oligoadenylates chiral at phosphorus: enzymatic synthesis, properties, and biological activities of 2',5'-phosphorothioate trimer and tetramer analogues synthesized from (SP)-ATP alpha S. 399 75

Primary and secondary immunizations with live, attenuated yellow fever virus vaccine (17D strain) were performed in order to study the course of appearance of virus-neutralizing antibodies and immunoglobulin M (IgM) and IgG antibodies directed against the virus and the interferon-dependent enzyme 2',5'-oligoadenylate synthetase (2',5'AS) activity, determined in homogenates of peripheral B and T lymphocytes. From cellular ATP, this enzyme generates 2',5'-oligoadenylates which mediate degradation of viral mRNA by stimulation of a latent RNase. By day 4 after the first immunization, the earliest and highest 2',5'AS activity was present in the T-lymphocyte fraction. By day 7, the enzyme activity was highest in the B-lymphocyte fraction. Virus-neutralizing antibodies appeared on day 7, and IgM antibodies were present on day 12. After the second immunization, performed 2 years +/- 2 months later, the only significant increase in 2',5'AS activity was observed in the T-lymphocyte fraction. Virus-neutralizing antibodies were present from day 1, whereas no IgM antibodies were detected. By day 12, 80% of the vaccines were IgG positive. In the primary and secondary (memory) immune responses, 2',5'AS activity is expressed in the T-lymphocyte fraction prior to the appearance of antibodies directed against the virus and may serve as an early and sensitive marker of an ongoing virus infection which is otherwise difficult to detect. No change in conventional laboratory analysis parameters, such as in differential blood cell counts or total IgA, IgG, and IgM, disclosed the immune activity in either the primary or the secondary immunization.
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PMID:Lymphocytic 2',5'-oligoadenylate synthetase activity increases prior to the appearance of neutralizing antibodies and immunoglobulin M and immunoglobulin G antibodies after primary and secondary immunization with yellow fever vaccine. 766 76

2',5'-Oligoadenylates (2-5A) have an essential role in the establishment of the antiviral state of a cell exposed to virus infection. The key enzymes of the 2-5A system are the 2-5A forming 2',5'-oligoadenylate synthetase (2-5OAS), the activity of which depends on the presence of viral or cellular double-stranded RNA (dsRNA), and the 2-5A-activated ribonuclease (RNase L). Basic research in recent years has shown that the 2-5A system is a promising target for anti-HIV chemotherapy, particularly due to its interaction with double-stranded segments within HIV RNA. Two new strategies have been developed which yield a selective antiviral effect of 2-5A against HIV-1 infection: (1) development of 2-5A analogues displaying a dual mode of action (activation of RNase L and inhibition of HIV-1 RT) and (2) intracellular immunization of cells against HIV-1 infection by application of the HIV-1-LTR--2-5OAS hybrid gene. A further strategy is the inhibition of DNA topoisomerase I by longer 2-5A oligomers.
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PMID:The 2-5A system and HIV infection. 791 4

The PRL receptor (PRL-R) signals through the Janus tyrosine kinases (JAK) and other non-JAK tyrosine kinases, some of which are preassociated with the PRL-R. To clone PRL-R interacting proteins, the intracellular domain (ICD) of the long form of the PRL-R was used in a yeast two-hybrid screen of a human B cell cDNA library. One PRL-R interacting protein was identified as the 42-kDa form of the enzyme 2',5'-oligoadenylate synthetase (OAS). The in vivo interactions in yeast were further confirmed by an in vitro interaction assay and by coimmunoprecipitation in transfected mammalian cells. Functionally, OAS reduced the basal activity of two types of promoters in transiently transfected COS-1 cells. In the presence of PRL, OAS inhibited PRL induction of the immediate early IRF-1 (interferon-regulatory factor 1) promoter, but not PRL induction of the differentiation-specific beta-casein promoter, suggesting that OAS exerts specific effects on immediate early gene promoters. The inhibitory effects of OAS were accompanied by a reduction in PRL-inducible Stat1 (signal transducer and activator of transcription 1) DNA binding activity at the IRF-1 GAS (interferon-gamma-activated sequence) element. These results demonstrate a novel interaction of OAS with the PRL-R and suggest a role for OAS in modulating Stat1-mediated signaling to an immediate early gene promoter. Although previously characterized as a regulator of ribonuclease (RNase) L antiviral responses, OAS may have additional effects on cytokine receptor signal transduction pathways.
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PMID:Association of 2',5'-oligoadenylate synthetase with the prolactin (PRL) receptor: alteration in PRL-inducible stat1 (signal transducer and activator of transcription 1) signaling to the IRF-1 (interferon-regulatory factor 1) promoter. 1067 1

A study was undertaken to evaluate the efficacy of an adenoviral construct expressing the murine interferon-beta (IFN-beta) transgene (Ad:IFN-beta) against herpes simplex virus type 1 (HSV-1) infection in a primary trigeminal ganglion (TG) cell culture. The transduction efficiency ranged from 0.2 to 11.0% depending on the multiplicity of infection (m.o.i.) of the adenoviral vector (0.5-50.0). Moreover, neurons were the main target of the adenoviral transduction. TG cultures transduced with Ad:IFN-beta displayed up to a 19-fold reduction in viral titers compared with cells transduced with an Ad:Null or nontransduced TG culture controls. Transduction with Ad:IFN-beta up-regulated two critical antiviral genes, double-stranded RNA-dependent protein kinase R (PKR) and 2',5'-oligoadenylate synthetase (OAS). The absence of PKR or RNase L (downstream effector molecule of OAS) attenuated Ad:IFN-beta efficacy against HSV-1 replication, implicating a critical role for PKR and OAS/RNase systems in the establishment of IFN-induced resistance against HSV-1 in TG cells.
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PMID:The murine double-stranded RNA-dependent protein kinase PKR and the murine 2',5'-oligoadenylate synthetase-dependent RNase L are required for IFN-beta-mediated resistance against herpes simplex virus type 1 in primary trigeminal ganglion culture. 1295 Oct 27

It is likely that human genetic differences mediate susceptibility to viral infection and virus-triggered disorders. OAS genes encoding the antiviral enzyme 2',5'-oligoadenylate synthetase (2'5'AS) are critical components of the innate immune response to viruses. This enzyme uses adenosine triphosphate in 2'-specific nucleotidyl transfer reactions to synthesize 2',5'-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication. We showed elsewhere that constitutive (basal) activity of 2'5'AS is correlated with virus-stimulated activity. In the present study, we asked whether constitutive activity is genetically determined and, if so, by which variants. Analysis of 83 families containing two parents and two children demonstrated significant correlations between basal activity in parent-child pairs (P<.0001) and sibling pairs (P=.0044), but not spousal pairs, suggesting strong genetic control of basal activity. We next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism at the exon 7 splice-acceptor site (AG or AA) of the OAS1 gene. At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity (0.44 vs. 0.20; P=3 x 10(-11)). Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes (tested by analysis of variance; P=1 x 10(-14)). Allele G generates the previously described p46 enzyme isoform, whereas allele A ablates the splice site and generates a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection.
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PMID:Variation in antiviral 2',5'-oligoadenylate synthetase (2'5'AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene. 1573 9

The latent ribonuclease RNase L and the interferon-inducible 2',5'-oligoadenylate synthetase (OAS) have been implicated in the antiviral response against hepatitis C virus (HCV). However, the specific roles of these enzymes against HCV have not been fully elucidated. In this study, a scarce endogenous expression and RNA degrading activity of RNase L in human hepatoma Huh7 cells enabled us to demonstrate the antiviral activity of RNase L against HCV replication through the transient expression of the enzyme. The antiviral potential of specific members of the OAS family was further examined through overexpression and RNA interference approaches. Our data suggested that among the members of the OAS family, OAS1 p46 and OAS3 p100 mediate the RNase L-dependent antiviral activity against HCV.
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PMID:The ribonuclease L-dependent antiviral roles of human 2',5'-oligoadenylate synthetase family members against hepatitis C virus. 2319 81